Malaria remains the most common serious illness of children in Africa. There is increasing interest in the use of chemopreventive strategies for infants and young children, generally intermittent preventive therapy (IPT) with sulfadoxine-pyrimethamine (SP). However, the optimal drugs or dosing strategies for IPT have not been identified. Concurrently, standard policy for HIV-infected children now includes chemoprophylaxis with trimethoprim-sulfamethoxazole (TS), which offers a high degree of protection against malaria. Given increasing levels of resistance to the antifolate drugs (TS and SP), newer drugs, such as the arteminsininbased combination therapy dihydroartemisinin-piperaquine (DP), may offer better preventive efficacy. Considering this background, it is an urgent priority to identify optimal chemopreventive strategies for malaria in African children, as well as assess potential drawbacks of different regimens, such as increased toxicity or an increased risk of malaria after discontinuation of chemoprevention (rebound). We will compare the efficacy and safety of three chemopreventive strategies with no chemoprevention, which is the current standard of care, among infants and children in Uganda. The specific aims will be: 1) to compare the incidence of malaria among infants and children enrolled at 4-12 months of age and randomized to receive no chemoprevention, daily TS, monthly SP, or monthly DP; 2) to compare the incidence of adverse events among infants and children enrolled at 4-12 months of age and randomized to receive no chemoprevention, daily TS, monthly SP, or monthly DP; and 3) to compare the incidence of malaria among children for 1 year following intervention with no chemoprevention, daily TS, monthly SP, or monthly DP. This study will be a randomized, open-label, trial of 800 HIV-uninfected infants randomized to equal numbers of each intervention arm. Participants will be followed for all routine and acute medical care until they reach the age of 36 months. Chemoprevention will be stopped at 24 months of age to allow for 1 additional year of followup post-intervention. The primary study endpoint will be the incidence of symptomatic malaria. Secondary endpoints will include incidence of complicated malaria, diarrheal illnesses and respiratory tract infections; prevalence of asymptomatic parasitemia, anemia, and gametocytemia; and incidence of adverse events to study drugs.